Targeting Bruton s Tyrosine Kinase (BTK)

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1 Targeting Bruton s Tyrosine Kinase (BTK) Lapo Alinari, MD, PhD 4 th International Conference, Translational Research in Oncology Forli, November 9-11/2016 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

2 Conflict of Interest for Lapo Alinari Investigator role in clinical trials Research Support Employee Consultant Major Stockholder Scientific Advisory Board Pharmacyclics (an AbbVie Company), Merck, Bristol-Myers Squibb BetaCat Pharmaceuticals None None None None

3 Objectives Explore the B-cell receptor signaling pathway Discuss BTK as a therapeutic target Discuss activity of and resistance to BTK inhibitors in the treatment of lymphoid malignancies Identify mechanisms to improve upon BTK inhibition

4 Objectives Explore the B-cell receptor signaling pathway Discuss BTK as a therapeutic target Discuss activity of and resistance to BTK inhibitors in the treatment of lymphoid malignancies Identify mechanisms to improve upon BTK inhibition

5 B-cell receptor signaling pathway ITAM: immunoreceptor tyrosine-based activation motif Zhong Y et al. Seminars in Hematology 2014

6 B-cell receptor signaling pathway BCR AP1 NFAT NF-kB Cyclin D1 Cyclin A Cyclin E p53 p21 p16 P19 PTPRO TNFα CD154 IL2 IL3 IL4 IL5 INFϒ c-myc Bcl2 Bax Bcl-xl IRF4 Blimp1 ILs

7 B-cell receptor signaling Activation of B-cell receptor signaling Antigen dependent Antigen independent Normal B cells Chronic lymphocytic leukemia (CLL) Mantle cell lymphoma (MCL) ABC-diffuse large B-cell lymphoma (ABC-DLBCL) 7

8 Objectives Explore the B-cell receptor signaling pathway Discuss BTK as a therapeutic target Discuss activity of and resistance to BTK inhibitors in the treatment of lymphoid malignancies Identify mechanisms to improve upon BTK inhibition

9 BTK as a therapeutic target BTK is a member of the Tec family kinases and plays a central role in B-cell receptor signaling pathway. Although BTK is expressed in multiple hematopoietic cells the primary defect in BTK-/- mice is B-cell specific. Loss of BTK function in humans give rise to X-linked agammaglobulinemia, an inherited disorder characterized by complete lack of mature B cells. BTK was identified in preclinical models as an essential signaling kinase for survival of chronic lymphocytic leukemia (CLL) and certain B-cell lymphomas.

10 Pros and cons of targeting BTK Pros: BCR signaling is vital to malignant B cell survival, proliferation BTK activation leads to activation of PI3K, PLCγ2, MAPK, and NF-kB pro-survival pathways Mouse models of BTK deficiency suggest predominantly a B-cell defect, without impairment of T-cells Cons: Targeting BTK may enhance immune suppression due to influence on normal B-cells function, neutrophils maturation, and NK cells mediated ADCC

11 Ibrutinib: a potent Btk Inhibitor N NH2 N N N O Binds irreversibly to cysteine-481 in Btk Inhibits BCR signaling Active in preclinical models of CLL and lymphoma Orally available N O Honigberg LA et al. PNAS 2010 Herman S et al. Blood 2011 Ponader L et al. Blood 2012 Once daily dosing results in 24-hr sustained target inhibition

12 Honigberg LA et al. PNAS 2010 Interleukin-induced tyrosine kinase

13 Objectives Explore the B-cell receptor signaling pathway Discuss BTK as a therapeutic target Discuss activity of and resistance to BTK inhibitors in the treatment of lymphoid malignancies Identify mechanisms to improve upon BTK inhibition

14 Ibrutinib clinical development Phase I open-label study of ibrutinib in relapsed refractory B-cell malignancies Patient characteristics N = 56 Overall response rate Histologic subtype: Follicular lymphoma % CLL % Mantle cell lymphoma 9 78% DLBCL 7 28% Other 8 50% Advani RH et al. JCO 2013

15 Disease focus Chronic lymphocytic leukemia Mantle cell lymphoma Diffuse large B-cell lymphoma

16 Chronic lymphocytic leukemia (CLL) CLL is the most prevalent adult leukemia and is characterized by a progressive accumulation of functionally incompetent B cells Presentation usually indolent Standard treatment regimen for symptomatic CLL patients: Options include purine analogs, alkylating agents, monoclonal antibodies, ibrutinib. Options at relapse include ibrutinib, monoclonal antibodies, bcl2 inhibitor, PI3K inhibitors, CDK inhibitors, steroids, chemo-immunotherapy, enrollment in a clinical trial, transplant

17 A Phase Ib/II Study of Ibrutinib in Relapsed CLL PCYC-1102-CA N = 86 Age, years ECOG Status Median (Range) 70 years, (%) (37 82) 35% 41% 56% 2% Median Prior Therapies 4 (1-12) β 2 Microglobulin > 3mg/L, 49% % Rai Stage III/IV at Baseline 65% Prognostic Markers, % IgV H unmutated del(17p13.1) del(11q22.3) 85% 35% 39% Byrd et al NEJM. 2013

18 A Phase Ib/II Study of Ibrutinib in Relapsed CLL PFS at 26 months 75% OS at 26 months 75% Byrd JC et al. NEJM. 2013

19 Progression-Free Survival (%) Phase III study of ibrutinib versus ofatumomab in patients with relapsed/refractory CLL (RESONATE) Ibrutinib Ofatumumab 78% reduction in the risk of progression with ibrutinib (p<0.001) No. at risk Ibrutinib: Ofatumumab: Months Byrd JC et al. NEJM 2014

20 Ibrutinib (n=195) Ofatumumab (n=196) Overall Survival (%) Month 57% reduction in death with ibrutinib (p=0.0049) Phase III study of ibrutinib versus ofatumomab in patients with relapsed/refractory CLL (RESONATE) Byrd JC et al. NEJM 2014

21 Phase III study of ibrutinib versus chlorambucil in patients with treatment naive CLL (RESONATE-II) 84% reduction in the relative risk of progression with ibrutinib 18 month PFS 90% vs 52% Burger JA et al. NEJM 2015

22 Patients who survived (%) Phase III study of ibrutinib versus chlorambucil in patients with treatment naive CLL (RESONATE-II) 84% reduction in relative risk of death with ibrutinib 24 month OS 98% vs 85% Burger JA et al. NEJM 2015

23 3-year follow-up of treatment-naïve and relapsed CLL patients receiving ibrutinib Byrd JC et al, Blood 2015

24 Limited duration of response to ibrutinib: del17p 30-months PFS No 17p-/11q- 89.0% 17p- 45.9% Byrd JC et al, Blood 2015

25 Prolonged lymphocytosis during ibrutinib treatment does not indicate suboptimal response Woyach JA et al, Blood 2014

26 Mantle Cell Lymphoma (MCL) MCL is a rare and incurable B-cell non-hodgkin s lymphoma Presentation can be indolent or aggressive No standard front-line regimen: Rituximab(R)-chemo, R-chemo followed by ASCT Consolidation with autologous transplant in first remission may prolong progression-free survival Options at relapse include ibrutinib, bortezomib, R- bendamustine, lenalidomide, mtor inhibitor, enrollment in a clinical trial, transplant in selected patients

27 The NEW ENGLAND JOURNAL of MEDICINE established in 1812 august 8, 2013 vol. 369 no. 6 Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma Michael L. Wang, M.D., Simon Rule, M.D., Peter Martin, M.D., Andre Goy, M.D., Rebecca Auer, M.D., Ph.D., Brad S. Kahl, M.D., Wojciech Jurczak, M.D., Ph.D., Ranjana H. Advani, M.D., Jorge E. Romaguera, M.D., Michael E. Williams, M.D., Jacqueline C. Barrientos, M.D., Ewa Chmielowska, M.D., John Radford, M.D., Stephan Stilgenbauer, M.D., Martin Dreyling, M.D., Wieslaw Wiktor Jedrzejczak, M.D., Peter Johnson, M.D., Stephen E. Spurgeon, M.D., Lei Li, Ph.D., Liang Zhang, M.D., Ph.D., Kate Newberry, Ph.D., Zhishuo Ou, M.D., Nancy Cheng, M.S., Bingliang Fang, Ph.D., Jesse McGreivy, M.D., Fong Clow, Sc.D., Joseph J. Buggy, Ph.D., Betty Y. Chang, Ph.D., Darrin M. Beaupre, M.D., Ph.D., Lori A. Kunkel, M.D., and Kristie A. Blum, M.D. Wang ML et al, NEJM 2013

28 Patient Characteristics Bortezomib-Naïve (N=63) Bortezomib-Exposed (N=48) Total (N=111) Median Age 66 (46-83) 69 (40 84) 68 (40 84) Median number prior regimens: (Range) 3 regimens 2 (1-5) 31 (49%) 3 (1-5) 30 (62%) 3 (1-5) 61 (55%) Simplified MIPI Low risk (0-3) Intermediate (4-5) High risk (6-11) 9 (14) 24 (38) 30 (48) 6 (12) 18 (38) 24 (50) 15 (14) 42 (38) 54 (49) Refractory (less than PR to last tx) 27 (43) 23 (48) 50 (45) Wang ML et al, NEJM 2013

Percent of patients (%) Overall response Efficacy Population n=111, Median Follow Up ~15.3 months (range, 1.9-22.

29 Percent of patients (%) Overall response Efficacy Population n=111, Median Follow Up ~15.3 months (range, ) 100 CR PR 80 68% 68% 68% Wang ML et al, NEJM Bortezomibnaïve (n=63) Bortezomibexposed (n=48) Total (n=111)

30 Ibrutinib survival curves Estimated median PFS: 13.9 months Median PFS: 13 months Estimated median OS: 22.5 months Wang ML et al, NEJM 2013

31 Outcomes for patients relapsing/progressing on ibrutinib Cheah CY, Ann Onc, discontinued ibrutinib (or R-ibrutinib) 19% primary progression 47% relapsed 14% AE 10% transplant 10% patient choice Median 6.5 cycles (1-43) 31 patients salvage with ORR 32% regardless of regimen MEDIAN OS 8.4 months Martin P, Blood, discontinued ibrutinib 32% primary progression 54% relapsed 2% AE 1% patient choice Median 4.7 cycles ( ) 73 patients salvage with ORR 36% no differences in median OS with any specific regimen MEDIAN OS 2.9 months

32 Diffuse large B-cell lymphoma (DLBCL) DLBCL is the most common NHL remarkable heterogeneity with diverse histologic and molecular variants: germinal center B-cell (GCB) vs activated B-cell (ABC)-DLBCL. ABC-DLBCL, but not GC-type, relies on constitutive activation of NF-kB for proliferation and survival and has been associated with worse outcome Standard front-line regimen: R-CHOP High dose chemotherapy followed by autologous stem cell transplant (ASCT) is standard for DLBCL patients with chemosensitive relapse DLBCL patients that relapse after ASCT have a very poor prognosis with reported median OS of 5-10 months Options at relapse after ASCT include enrollment in a clinical trial, chemotherapy, ibrutinib, lenalidomide

33 Lenz et al, N Engl J Med Molecular Subtypes of DLBCL

34 Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma Nature Medicine 2015 Wilson WH et al, Nat Med 2015

35 Patient characteristics (Total 70 pts, 29 ABC, 20 GCB, 16 Unclassifiable, 5 Unknown) Characteristics Total (N=70) ABC (N=29) GCB (N=20) Median Age (range) 64 (28-92) 62 (34-89) 65 (28-92) IPI (HI/High) 37 (59%) 61% 58% Prior regimens median (range) 3 (1-7) 3 (1-7) 3.5 (1-7) Prior ASCT 16 (23%) 17% 30% Refractory disease 38 (54%) 41% 70% Wilson WH et al, Nat Med 2015

36 Ibrutinib improves ORR 25% (20/80) PFS/OS in ABC DLBCL CR 10% (8/80) compared to GC-subtype ORR ABC: 37%/CR ORR 37%CR 16% 16% GC: ORR 5% ORR 5% **3 ongoing responses at 32, 36, & 52 months

37 Percent Response (CR + PR) CD79B mutant ABC DLBCL predicts higher rate of response to ibrutinib /7 10/29 4/5 0 0/4 0/4 CD79B: Mutant WT Mutant WT WT MYD88: WT WT Mutant Mutant Mutant CARD11: Wilson WH et al, Nat Med 2015 WT WT WT WT Mutant

38 Primary and acquired resistance to ibrutinib

39 Characteristics of 6 CLL patients with acquired resistance to ibrutinib Patient Age No. Prior Therapi es Cytogenetics Study Treatment Duration on Ibrutinib Best Respons e Identified Mutation del(17p13.1), mg qd 621 days PR C481S, BTK del(17p13.1), complex karyotype 420 mg qd 673 days PR R665W, PLCγ del(11q22.3) complex karyotype BR x 6 cycles, 420 mg qd Ofatumumab x 24 weeks, 420 mg qd 388 days CR C481S, BTK 674 days CR C481S, BTK del(17p13.1), complex karyotype 840 mg qd 868 days PR C481S, BTK del(17p13.1), complex karyotype Ofatumumab x 24 weeks, 420 mg qd 505 days PR L845F, PLCγ2; C481S, BTK Woyach J et al. NEJM 2014

40 BTK and PLCϒ2 mutations Ibrutinib Lyn SYK I I g g H H P P C C D D A B BTK PLCγ2 CARD11 BCL10 MALT1 WES discovery of BTK and PLCG2 mutations: Woyach J et al, NEJM 2014 Characterization of ibrutinib resistant disease: Maddocks et al, JAMA Oncol 2015 Modeling PLC ϒ2 mutation: Liu et al, Blood 2015

41 What is the pattern of ibrutinib failure? Patients BTK PLCγ2 Both 11/ Maddocks K et al. Jama Oncol 2015

42 Mechanisms of ibrutinib resistance in MCL Balasubramian D, et al. (ASH 2014, abstract 78) 25 patients refractory to ibrutinib in multi-center, phase 2 trial 23 patients had pre-treatment tumor or CD19-selected peripheral blood samples sequenced No BTK C481S mutations and 1 PLCγ2 mutation identified Chiron D, et al. (Cancer Discovery, 2014) 8 patients with ibrutinib failure with BTK and PLCγ2 mutational analysis at recurrence 2 patients with C481S mutations, treated for 14 and 30 months 6 patients without mutations, all treated < 5 months Martin P, et al. (Blood, 2016) 114 patient with ibrutinib failure 10 patients had BTK and PLCγ2 mutational analysis at recurrence 2 patients with C481S mutations, treated for 12.1 and 12.6 months 8 patients without mutations, treated months 43

43 Mechanisms of ibrutinib resistance in MCL CARD11 mutation Identified in 1 patient at relapse (Wu et al, ICML 2015) Genetic lesions in the alternative NF-kB pathway occur in patients with MCL (Chiron D et al, Cancer Discovery 2014) TRAF2 (6%), TRAF3 (10%), BIRC2, BIRC3, MAP3K14 BTK WT Despite ongoing inhibition of BTK, high level of PI3K- AKT expression and activation has been found (Chiron D et al, Cancer Discovery 2014) 44

44 What we know about single agent ibrutinib Most CLL patients have durable remissions to ibrutinib Acquired mutations in BTK and PLCϒ2 appear to be the main driver to ibrutinib resistance in CLL 30-40% of MCL patients do not respond to ibrutinib and 10-20% have very short remissions. Among the MCL patients that achieve a durable remission, relapse appears universal. Responses in DLBCL is limited to a subset of patients. Duration of response in DLBCL is also short

45 Objectives Explore the B-cell receptor signaling pathway Discuss BTK as a therapeutic target Discuss activity of and resistance to BTK inhibitors in the treatment of lymphoid malignancies Identify mechanisms to improve upon B-cell receptor inhibition

absence of irreversible inhibition of other kinases (TEC, EGFR, ITK) At a

46 Novel BTK inhibitors: ACP-196 in CLL Acalabrutinib (ACP-196) is a second generation, selective, irreversible inhibitor of BTK characterized by the absence of irreversible inhibition of other kinases (TEC, EGFR, ITK) At a median follow up 14.3 months, ORR 95% (85% PR) including 17p del Byrd JC et al. NEJM 2016

47 ACP-196 in lymphoma preclinical models Median PFS 22.5 days 24 dogs with spontaneous DLBCL received escalating dose of ACP-196 (range mg/kg BID) Harrington B, et al. PlosOne 2016

48 Rationale for combination therapy Improved ORR and convert PR to CR Deeper remissions = longer PFS/OS? Prevent relapse With conventional chemotherapy With biological agents Combination therapy

49 What does chemotherapy add to ibrutinib in CLL? Chanan- Khan A et al, Lancet Oncol 2016 Ibrutinib+BR Phase 3 Number 289 Age 64 17p permitted? no # prior regimens 1 11 (2) ORR 83% CR 10% Median follow up 17 mo PFS 72% at 24 mo OS 88% at 24 mo

50 What does chemotherapy add to ibrutinib in CLL? Ibrutinib+BR Ibrutinib alone Phase 3 3 Number Age p permitted? no yes # prior regimens 1 11 (2) 1-12 (4) ORR 83% 90% CR 10% 7% Median follow up 17 mo 36 mo PFS 72% at 24 mo 69% at 30 mo OS 88% at 24 mo 79% at 30 mo Chanan- Khan A et al, Lancet Oncol 2016 Byrd JC et al, NEJM 2014

51 What does chemotherapy add to ibrutinib in lymphoma? ABC-DLBCL Wang ML et al, NEJM 2013 Wilson WH et al, Nat Medicine 2015 Maddocks K et al, Blood 2015 Ibrutinib+BR ORR 37% 37% CR 27% 16% Ibrutinib alone Median PFS 2.5 months 2 months Median OS Not provided 10 months MCL ORR 94% 68% CR 76% 21% Median PFS Not reached 13.9 months Median OS Not reached 22.5 months

52 Ibrutinib + Rituximab for patients with high risk CLL 40 patients (some previously untreated) ORR 95% (8% CR) Proportion Surviving No: del 17p del 17p Months Progression Free Survival 18 month PFS 78% 0.00 No: del 17p del 17p Months Overall Survival 18 month OS 84% Burger JA, et al. Lancet Oncol 2014 PFS at 30 months 69%; OS 79%; Byrd JC Blood 2015

53 In vivo ibrutinib and an anti-pd-1 blocking agent controls BTK resistant B cell lymphoma No treatment Ibrutinib Anti PD-1 Combo Sagive- Barfi et al. PNAS 2015

54 Conclusions BTK inhibitors have dramatically changed the treatment paradigm for CLL Ibrutinib has high single agent activity in several subtypes of NHL but most patients ultimately relapse and survival after relapse is short Multiple mechanisms of resistance likely exist, and these are better defined in CLL than B-cell NHL How should we treat ibrutinib resistant patients? Clinical trials Prevention Transplant Combination Therapy 2 nd generation inhibitors

55 The new James Cancer Hospital 56

56 Thank You Interested in a collaboration? Interested in a research experience? Please contact me: Lapo.Alinari@osumc.edu To learn more about Ohio State s cancer program, please visit cancer.osu.edu or follow us in social media:

Supplementary Appendix

Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib